Glutathione-s-transferases (GSTs) are a group of multi-functional proteins which play an important role in the biotransformation of many different biologically active compounds, including agents which damage DNA, such as chemotherapeutic drugs, see Mannervik, B., Adv. Enzymol. Relat. Areas Mol. Biol. 57: 357-417 (1985). Indeed, it is known that GSTs are usually associated with the detoxification by conjugation of genotoxic and cytotoxic xenobiotic electrophiles derived from drugs, carcinogens and environmental pollutants, see Glutathione transferases; H. Sies and B. Ketterer (eds.), Glutathione Conjugation. Academic Press, New York, pp. 74-135 (1988).
On the basis of physical and immunological properties and substrate specificities and protein structure, the human GSTs have been divided into three distinct classes, named alpha, mu and pi, see Mannervik B., et al, Proc. Natl. Acad. Sci. U.S.A. 82: 7202-7206 (1985).
It is an object of this invention to employ glutathione-s-transferase activity as a measure of drug resistance.
How this and other objects of this invention are achieved will become apparent in the light of the accompanying disclosure, including the drawing which graphically illustrates the subject invention. In at least one embodiment of the practices of this invention at least one of the objects of this invention will be achieved.
Cellular reduced glutathione, i.e. the co-substrate for GSTs, and GST activity in general, i.e. total activity estimated using 1-chloro-3,4-dinitrobenzene (CDNB) as a substrate, has been shown to be involved in the mechanism of chemotherapeutic drug resistance, see Johnston et al, J. Natl. Can. Inst. 82: 776-779 (1990) and Lai, G-M, et al, J. Natl. Can. Inst. 81: 535-539 (1989).
Chemotherapeutic agents, such as chlorambucil cisplatin, nitrosoureas and other chemotherapeutic drugs that can damage DNA or other cellular macromolecules, such as RNA or protein, are electrophiles which can be conjugated with glutathione directly or indirectly via GST activity. Hence, high levels of glutathione and/or GST activity provide a mechanism of drug resistance because cells having high levels have increased opportunities to remove the drugs before the drugs can cause genotoxicity or cytotoxicity or other adverse effects. Heretofore, however, it has not been known whether any one of the known GST isozymes, either the alpha, pi or the mu class, is more specifically involved in conjugating chemotherapeutic drugs with glutathione.